Method and composition for treating obesity comprising dehydroepiandrosterone (DHEA), or a derivative thereof, and an anorectic agent

ABSTRACT

The invention describes a method and composition for treating obesity or related disorders in animals using an anorectic agent and dehydroepiandrosterone (DHEA). The composition effectively diminishes caloric intake, may alter metabolism, weight gain, or a combination thereof.

DESCRIPTION

A method and composition for treating obesity and related disorders inanimals comprising dehydroepiandrosterone (DHEA), or a derivativethereof, and an anorectic agent.

FIELD OF THE INVENTION

This invention describes an effective method and composition fortreating obesity and related disorders in humans and animals, such asdogs, cats, or any other suitable animal, using DHEA or a derivativethereof and an anorectic agent. The method and composition are useful inveterinary as well as human applications.

BACKGROUND OF THE INVENTION

Obesity may be the major health problem of the Western world. Nearly 20%of the United States' adult population is overweight and its prevalenceis rising. The medical and economic importance of obesity go far beyondeffects on self-image. Obesity is the dominant risk factor for theexpression of adult-onset diabetes mellitus, and thus leads tocomplications of cardiovascular, renal, and peripheral vascular disease.Obesity is also a leading factor in the development of complicationsafter surgical procedures.

Although obesity is probably a common endpoint for a variety ofdisorders, all causes of obesity have at least a period of hyperphagiain which the subject eats more food than needed for the current energyneeds. Currently, there is no effective treatment for hyperphagia. Theagents used, at best, work for only a few weeks or are clinically unsafebecause of serious side effects.

This invention teaches the use of DHEA and one or more of the followinganorectic agents for the treatment of obesity and related disorders inanimals: fenfluramine hydrochloride (HCl), phentermine HCl,phendimetrazine tartrate, mazindol, diethylpropion HCl, and fluoxetineHCl. DHEA has been evaluated for its ability to modify food intakeand/or weight when administered individually, but not in combinationwith the anorectic drugs disclosed in this invention. There was noappreciation in the art that the combined use of DHEA and one or more ofthe disclosed anorectic agents would have a significant and dramaticeffect on the treatment of obesity and related disorders.

Dehydroepiandrosterone (DHEA) and its sulphated derivative, both majorsecretory products of the human adrenal, are naturally occurringsteroids. Traditionally, DHEA has been called an adrenal androgenbecause it can be metabolized in the periphery to testosterone. DHEAitself cannot interact with the androgen receptor, and thus is not anandrogen.

The effect of DHEA on food intake and obesity in the Zucker rat wasstudied by Cleary M. P., "The Antiobesity Effect ofDehydroepiandrosterone in Rats," Proceedings of the Society forExperimental Biology and Medicine, 196:8-16 (1991). This referencereports results showing administration of DHEA to rats caused a weightloss independent of food intake. Conflicting reports have been reportedby others, who found that administration of DHEA decreased caloricintake in obese Zucker rats, but not in the lean animal. Wright et al.,"Divergent Effect of Dehydroepiandrosterone on Energy Intakes of ZuckerRats," Physiology & Behavior, 53:39-43 (1993). The conflicting reportsmay reflect the different methods employed by the two groups incalculating food intake for the animals. Cleary measured dailycumulative food intake, in which changes are measured at the end of aperiod of time such as two weeks. Wright et al. measured daily intakeand weight change for 7-8 days. An initial change was found within 24hours. As the animals' weight and metabolism may have already changedwith administration of the drug at the end of a two week period, themethod of Wright et al. more clearly reflects the effect of the drug onthe animal.

DHEA was also evaluated for its effect on obesity, serum lipids, andbody fat in humans. Nestler et al., "Dehydroepiandrosterone ReducesSerum Low Density Lipoprotein Levels and Body Fat but Does not AlterInsulin Sensitivity in Normal Men," J. Clin. Endocrinol. Metab.,66:57-61 (1988). Results showed DHEA in a divided dose of 1600mg/person/day, corresponding to a dose of about 22 mg/kg/day, has noeffect on either food intake or body weight in lean subjects, althoughit may have a slight effect on body fat content. Other researchers wereunable to repeat the positive results. Welle et al., "Failure ofDehydroepiandrosterone to Influence Energy and Protein Metabolism inHumans," Journal of Clinical Endocrintogy, 71:1259-1264 (1990).

The anorectic drugs used in this invention include fenfluramine HCl,phentermine HCl, phendimetrazine tartrate, mazindol, diethylpropion HCl,and fluoxetine HCl. Tachyphylaxis and tolerance have been demonstratedwith all drugs of this class used in the treatment of obesity.Physician's Desk Reference., 47th edition, page 1053 (Medical EconomicsData, Montvale, N.J., 1993), incorporated by reference. It has not beenestablished that the action of such drugs in treating obesity isprimarily one of appetite suppression, as other central nervous systemactions or metabolic effects may be involved. Physician's Desk Referenceat 1053. The drugs are not particularly effective, as the magnitude ofincreased weight loss of drug-treated patients over placebo-treatedpatients is only a fraction of a pound a week, with the rate of weightloss being greatest in the first weeks of therapy for both drug andplacebo-treated subjects and decreasing in succeeding weeks as toleranceto the anorectic agent develops. Physician's Desk Reference at 1053.

Fenfluramine HCl, chemically known asN-ethyl-α-methyl-3(tri-fluoromethyl)benzeneethanamine hydrochloride, isan anorectic agent differing from prototype anorectic drugs used in thetreatment of obesity in appearing to produce more central nervous systemdepression than stimulation. Physician's Desk Reference at 1949.Tolerance to the anorectic effect usually develops within a few weeks,requiring discontinuation of the use of the drug. Physician's DeskReference at 1949. The drug is commercially available under the tradename PONDIMIN® Tablets (A. H. Robins Co.).

Phentermine hydrochloride, chemically known as phenyltertiary-butylaminehydrochloride, is a sympathomimetic amine with pharmacologic activitysimilar to the prototype drugs of this class used in obesity, theamphetamines. Physician's Desk Reference at 1053 and 2305. The drug isan anorectic compound with actions including central nervous systemstimulation and elevation of blood pressure. Physician's Desk Referenceat 1053. Tolerance to the anorectic effect usually develops within a fewweeks, requiring discontinuation of the use of the drug. Physician'sDesk Reference at 1053. The drug is commercially available under thetrade names FASTIN® Capsules (SmithKline Beecham Pharmaceuticals) andADIPEX-P® (Gate Pharmaceuticals).

Phendimetrazine tartrate, chemically known as(+)-3,4-dimethyl-2-phenylmorpholine tartrate, is another anorectic drughaving an effect on appetite and the central nervous system. Physician'sDesk Reference at 710, 857, and 2618. Tolerance to the anorectic effectusually develops within a few weeks, requiring discontinuation of theuse of the drug. Physician's Desk Reference at 711. The drug iscommercially available under the trade names PRELU-2® (BoehringerIngelheim Pharmaceuticals, Inc.), BONTRIL® PDM and BONTRIL® SLOW-RELEASE(Carnrick Laboratories, Inc.), and PLEGINE® (Wyeth-Ayerst Laboratories).

Mazindol, chemically designated as5-(4-chlorophenyl)-2,5-dihydro-3H-imidazo[2,1-α]isoindol-5-ol, is animidazoisoindole anorectic agent. Physician's Desk Reference at 2126.Although an isoindole, mazindol has pharmacologic activity similar tothe prototype drugs used in obesity, the amphetamines. Physician's DeskReference at 2126. Tolerance to the anorectic effect usually developswithin a few weeks, requiring discontinuation of the use of the drug.Physician's Desk Reference at 2127. The drug is commercially availableunder the trade name SANOREX® (Sandoz Pharmaceuticals Corp.).

Diethylpropion hydrochloride, chemically known as1-phenyl-2-diethylamino-1-propanone hydrochloride, is a sympathomimeticamine with actions including some central nervous system stimulation andelevation of blood pressure. Physician's Desk Reference at 1403.Tolerance to the anorectic effect usually develops within a few weeks,at which point the drug is discontinued. Physician's Desk Reference at1403. Diethylpropion HCl is commercially available under the trade namesTENUATE® and TENUATE DOSPAN® (Marion Merrell Dow Inc.).

Finally, fluoxetine HCl, chemically designated(±)-N-methyl-3-phenyl-3-[(α,α,α-trifluro-p-tolyl)oxy]propylaminehydrochloride, is a compound used as an antidepressant. Physician's DeskReference at 943. The drug influences serotonergic transmission, acharacteristic of anorectic agents. Van de Kar et al., "SerotonergicNeurons and Neuroendocrine Function," NIPS, 8:202-207 (1993).Significant weight loss can result with fluoxetine HCl treatment.Physician's Desk Reference at 944; Darga et al., "Fluoxetine's Effect onWeight Loss in Obese Subjects," Am. J. Clin. Nutr., 54:321-5 (1991); andVisser et al., "The Effect of Fluoxetine on Body Weight, BodyComposition and Visceral Fat Accumulation," Int. J. Obes., 17:247-53(1993). Fluoxetine HCl has not been systematically studied, in animalsor humans, for its potential for tolerance. Physician's Desk Referenceat 945-6. However, recent studies showed rapid development of tolerancewith administration of fluoxetine and fenfluramine. McGuirk et al.,"Effects of Chronically Administered Fluoxetine and Fenfluramine on FoodIntake, Body Weight and the Behavioural Satiety Sequence,"Psychopharmocology (Berl), 106:401-7 (1992). The drug is commerciallyavailable under the trade name PROZAC® (Dista Products Co.).

This invention fulfils a need in the art for an effective method fortreating obesity and related disorders in animals. The method, employinga composition comprising DHEA or a derivative thereof and an anorecticagent, diminishes caloric intake, may affect metabolism, or acombination thereof, to produce a weight loss for the treated subject.Other objects and advantages of the invention are set forth in thefollowing description. The accompanying drawings illustrate and,together with this description, explain the principle of the invention.

SUMMARY OF THE INVENTION

The present invention overcomes the problems and disadvantagesassociated with current strategies for treating obesity, such as thedevelopment of tolerance within a short period of time to the drugscurrently employed, and provides a new therapy for the treatment ofobesity and related disorders in animals. This invention describes theuse of DHEA or a derivative thereof and at least one anorectic agent incombination to produce weight loss in animals.

A further embodiment of the invention is the additional administrationof a glucocorticoid, along with the combination of DHEA or a derivativethereof and at least one anorectic agent, for the treatment of obesityand related disorders in animals.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1 through 10 describe experimental results comprisingadministration of DHEA or an anorectic agent, such as fenfluramine HCl,phentermine HCl, mazindol, and diethylpropion HCl, or a combination ofan anorectic agent and DHEA to lean and obese Zucker rats to determinethe effect of the treatments on food intake and weight loss of theanimals.

FIGS. 1A, 1B, 1C and 1D: The effect of fenfluramine and DHEA, givenindividually and in combination, on the caloric intake of carbohydrate,protein, and fat in lean Zucker rats is shown. Groups of lean rats werepresented bowls of food containing nearly pure carbohydrate, protein, orfat. After an initial control period, the rats received fenfluramine(Drug F) at 5/mg/kg/day, DHEA (Drug D) at 100 mg/kg/day, or bothfenfluramine and DHEA intraperitoneally daily for four days. A fourthgroup (control) received no drug. Caloric intake was measured andrecorded each day, with the first day of drug treatment day 0 and thefourth day of treatment day 3. Values are the mean +SEM. FIG. 1A showsthe total caloric intake, FIG. 1B shows the total protein intake, FIG.1C shows the total carbohydrate intake, and FIG. 1D shows the total fatintake, all measured at day 3.

FIGS. 2A, 2B, 2C and 2D: The effect of fenfluramine and DHEA, givenindividually and in combination, on the caloric intake of carbohydrate,protein, and fat in obese Zucker rats is shown. Groups of obese ratswere presented bowls of food containing nearly pure carbohydrate,protein, or fat. After an initial control period, the rats receivedfenfluramine (Drug F) at 5/mg/kg/day, DHEA (Drug D) at 100 mg/kg/day, orboth fenfluramine and DHEA intraperitoneally daily for four days. Afourth group (control) received no drug. Caloric intake was measured andrecorded each day, with the first day of drug treatment day 0 and thefourth day of treatment day 3. Values are the mean +SEM. FIG. 2A showsthe total caloric intake, FIG. 2B shows the total protein intake, FIG.2C shows the total carbohydrate intake, and FIG. 2D shows the total fatintake, all measured at day 3.

FIGS. 3A, 3B: The effect on the body weight of lean and obese Zuckerrats with administration of fenfluramine and DHEA, given individuallyand in combination, is shown. The weight of the lean rats described inFIG. 1 is given in FIG. 3A and the weight of the obese rats described inFIG. 2 is given in FIG. 3B. For each group the increment of weight isexpressed as a percentage of the initial body weight.

FIGS. 4A, 4B: The long-term effect of DHEA and fenfluramine, givenindividually and in combination, on the caloric intake and body weightof lean Zucker rats is shown. Four groups of four lean Zucker rats wereestablished. One group received 5 mg/kg/day fenfluramine; a second groupreceived rat chow supplemented with 0.6% DHEA; a third group received 5mg/kg/day fenfluramine and rat chow supplemented with 0.6% DHEA; and afourth group (control) received no medication. The weight of the foodconsumed on the indicated days is reported as calories in FIG. 4A andthe weight of the animals on the corresponding days is recorded in FIG.4B.

FIGS. 5A, 5B: The long-term effect of DHEA and fenfluramine, givenindividually and in combination, on the caloric intake and body weightof obese Zucker rats is shown. Four groups of four obese Zucker ratswere established. One group received 5 mg/kg/day fenfluramine; a secondgroup received rat chow supplemented with 0.6% DHEA; a third groupreceived 5 mg/kg/day fenfluramine and rat chow supplemented with 0.6%DHEA; and a fourth group (control) received no medication. The weight ofthe food consumed on the indicated days is reported as calories in FIG.5A and the weight of the animals on the corresponding days is recordedin FIG. 5B.

FIGS. 6A, 6B, 6C: The effect of mazindol and DHEA individually and incombination on the carbohydrate intake and body weight of lean Zuckerrats is shown. FIG. 6A shows the carbohydrate intake on day 3, FIG. 6Bshows the change in body weight on day 4, and FIG. 6C shows the totalcaloric intake on day 3 of the test. P value shows the difference fromthe control.

FIGS. 7A 7B: The effect of phentermine HCl and DHEA individually and incombination on fat intake and body weight of lean Zucker rats is shown.FIG. 7A shows the daily fat consumption and FIG. 7B shows body weightgain over the trial. P value shows the difference from the control.

FIGS. 8A, 8B, 8C: The effect of diethylpropion HCl and DHEA individuallyand in combination on fat intake, carbohydrate intake, and body weightof lean Zucker rats is shown. FIG. 8A shows the fat intake, FIG. 8Bshows the carbohydrate intake, and FIG. 8C shows the body weight changeover the time of the trial. P value shows the difference from thecontrol.

FIG. 9: The effect of corticosterone and DHEA individually and incombination on the body weight of lean Zucker rats is shown. Six groupsof animals were established: the first (control) group; a second groupreceiving an injection of 1 mg/kg/day corticosterone in sesame oil ("CpdB 1"); a third group receiving an injection of 5 mg/kg/daycorticosterone in sesame oil ("Cpd B 5"); a fourth group receiving adiet supplemented with 0.3% DHEA ("DHEA"); a fifth group receiving 1mg/kg/day corticosterone in sesame oil and a diet supplemented with 0.3%DHEA ("Cpd B 1+DHEA"); and a sixth group receiving an injection of 5mg/kg/day corticosterone in sesame oil and a diet supplemented with 0.3%DHEA ("Cpd B 5+DHEA").

FIGS. 10A, 10B, 10C, 10D: The effect of corticosterone and DHEAindividually and in combination on tissue weight of lean Zucker rats isshown. Six groups of animals were established as in FIG. 9. Four tissueswere removed from the animals: perirenal fat (A), epididymal fat (B),retroperitoneal fat (C), and soleus muscle (D). Each was weighed. Valuesare expressed as a percentage of the weight of the control tissue.

DESCRIPTION OF PREFERRED EMBODIMENTS

This invention describes dramatic diminishing of caloric intake andweight loss in animals with administration of a composition of DHEA or aderivative thereof and an anorectic agent. It was completely unexpectedthat the administration of DHEA or a derivative thereof and an anorecticagent would have such a synergistic effect on the treatment of obesityand related disorders. Furthermore, in sharp contrast to current methodsof treating obesity and related disorders, with administration of ananorectic agent in combination with DHEA, tolerance to the compositionover an extended period of time was not evident.

A further embodiment of the invention is the additional administrationof a glucocorticoid, such as corticosterone, along with the combinationof DHEA or a derivative thereof and the anorectic agent, for thetreatment of obesity and related disorders in animals. Theglucocorticoid is preferably administered in a dosage from about 1mg/kg/day up to about 50 mg/kg/day, and more preferably in a dosage fromabout 5 mg/kg/day up to about 25 mg/kg/day.

The composition can be administered orally or parenterally, or acombination of oral and parenteral administration can be used. Inaddition, DHEA or a derivative thereof and the one or more anorecticagents can be administered as an addition to the food of the animal.

Derivatives of DHEA, such as 16-substituted androstanes and16-substituted androstenes, are described in U.S. Pat. No. 5,001,119 toSchwartz et al., incorporated by reference. 17-hydroxy-steroids aredescribed in U.S. Pat. No. 4,898,694 to Schwartz et al., incorporated byreference. α-HET and β-HET analogs are described in U.S. Pat. No.4,897,390 to Ruhe, incorporated by reference. Such derivatives of DHEA,as well as metabolites of DHEA, such as Δ4-androstenedione, are usefulin the claimed invention.

The anorectic agents that can be employed in the invention includefenfluramine hydrochloride (HCl), phentermine HCl, phendimetrazinetartrate, mazindol, diethylpropion HCl, and fluoxetine HCl.

In the present invention, the D-L racemate of fenfluramine was used inthe experiments. The D-L and D isomers of fenfluramine differ inpotency: the D isomer is a much more potent compound. Garattini et al.,"From Fenfluramine Racemate to d-Fenfluramine," Human Obesity, Annals ofthe New York Academy of Sciences, vol. 499, Wurtman et al. eds., pages156-166 (The New York Academy of Sciences, New York, N.Y., 1987). Thus,the difference between using the D isomer and the D-L racemate offenfluramine is in the required dosage.

The composition of the invention can be administered either orally orparenternally. Preferable methods of administering the drugs are byinjections, food supplements, transdermal patches, or rectalsuppositories.

Pharmaceutically acceptable carriers for DHEA or a derivative thereof,the anorectic agent, or both, can also be employed. Such carriers can besterile liquids, such as water, alcohol, dimethylsulphoxide (DMSO),oils, including petroleum oil, animal oil, vegetable oil, peanut oil,soybean oil, mineral oil, sesame oil, and the like. Also useful arecarriers such as starch, sugar, lactose, magnesium stearate, stearicacid, cellulose, gelatin, talc, titanium dioxide, silica gel, tartaricacid, zinc stearate, povidone, glycerin, benzoic acid, iron oxide,silicone, and the like. Saline solutions, aqueous dextrose, and glycerolsolutions can also be employed as liquid carriers, particularly forinjectable solutions. Suitable pharmaceutical carriers are described inRemington's Pharmaceutical Sciences, 18th Edition (A. Gennaro, ed., MackPub., Easton, Pa., 1990), incorporated by reference.

The composition of the invention comprises at least one anorectic agentand DHEA in an amount effective in diminishing caloric intake,carbohydrate intake, fat intake, protein intake, or food intake, toproduce a weight loss for the animal. In particular, the anorectic agentand DHEA are present in amounts which in combination are synergisticallyeffective in treating obesity or a related disorder. Preferred dosagesof DHEA or a derivative thereof and one or more anorectic agents areeach from about 0.05 to about 200 mg/kg/day of each compound. Inparticular, the anorectic agent is administered in a dosage from about0.05 mg/kg/day up to about 100 mg/kg/day, and DHEA is administered in adosage from about 2.5 mg/kg/day up to about 100 mg/kg/day. Morepreferably, the anorectic agent is administered in a dosage from about 3mg/kg/day up to about 25 mg/kg/day, and DHEA is administered in a dosagefrom about 25 mg/kg/day up to about 100 mg/kg/day. Most preferably, fora composition comprising DHEA and fenfluramine HCl, DHEA is present inan amount from about 25 mg/kg/day up to about 100 mg/kg/day, anddl-fenfluramine HCl is present in an amount from about 5 mg/kg/day up toabout 10 mg/kg/day. If the d-isomer of fenflurmine is used, thefenflurmine is administered in a dosage of from about 2.5 mg/kg/day upto about 5 mg/kg/day.

This invention is applicable to treating any animal for obesity andrelated disorders. A further embodiment of the invention is the use ofthe disclosed compositions to produce lean animals, such as in livestockor veterinary applications.

The unexpected effect of the present invention is demonstrated in thefollowing experiments and is depicted in FIGS. 1-10. In theseexperiments, the Zucker rat was used as an animal model for theinvention because the animal is a good model of obesity, and because acolony of these animals was readily available. The obesity seen in theZucker fatty rat shares many characteristics with some forms of humanobesity; there is hyperphagia, hypoactivity, mild hyperglycemia, insulinresistance, and hypercorticosteronemia. White et al., "Responsiveness ofIsolated Adrenocortical Cells From Lean and Obese Zucker Rats to ACTH,"Am J. Physol, 255 (Endocrinol Metab 18):E229-E235 (1988); and Alarrayedet al., "Is There a Role for the Adrenals in the Development ofHypercholesterolemia in Zucker Fatty Rats," Am J. physiol, 263.(Endocrinol Metab 26):E287-E295 (1992). The animals have two phenotypes,obese and lean. The obese animal is characterized by hyperphagia,hyperinsulinism, and elevated lipids, with obesity beginning at age fourweeks.

In many of the experiments the animals were fed a "macronutrientselection diet." In this paradigm, each animal is presented with threebowls of food. The food in the first bowl contains 90% of its caloriesas carbohydrate, the food in the second bowl contains 90% of itscalories as protein, and the food in the third bowl contains 90% of itscalories as fat. Animals are allowed to choose between the three bowlsin the experiments. In general, both the obese and the lean animalsselected a similar diet: 40-50% fat, 20% protein, and 30-40%carbohydrate. Interestingly, this is similar to the composition of theusual human diet.

Having generally described the invention, a more complete understandingcan be obtained by reference to specific examples, which are providedherein for purposes of illustration only and are not intended to belimiting.

EXAMPLE 1

The effect of fenfluramine and DHEA, given both individually and incombination, on the caloric intake of carbohydrate, protein, and fat oflean Zucker rats was determined.

Female Zucker rats, aged 13-18 weeks, were obtained from the colonymaintained in the Department of Physiology at Louisiana State UniversityDental School in New Orleans, La. All animals were maintained on a 12hour light-dark cycle (lights on at 0600), with the temperaturemaintained at 22°±1° C.

Groups of lean rats were presented bowls of food containing nearly purecarbohydrate, protein, or fat. Each day consumption from each bowl wasmonitored, allowing a determination of total caloric, carbohydrate,protein, and fat intake. This enabled observing changes in an animals'choice of macronutrient.

After an initial control period, the rats received fenfluramine at5/mg/kg/day, DHEA at 100 mg/kg/day, or both fenfluramine and DHEAintraperitoneally. A fourth group (control) received no drug. Caloricintake was measured and recorded each day, with the first day oftreatment day 0 and the fourth day of treatment day 3. Values are themean +SEM. FIG. 1A shows the total caloric intake, FIG. 1B shows thetotal protein intake, FIG. 1C shows the total carbohydrate intake, andFIG. 1D shows the total fat intake, all measured at day 3.

The total intake of calories was not significantly affected by eitherDHEA or fenfluramine given individually. Fenfluramine given alonediminished carbohydrate intake. This was expected, as fenfluraminealters serotonin release and this affects carbohydrate preference.

The combination of fenfluramine and DHEA had a significant effect onboth total intake of calories and carbohydrate intake. Total caloricintake fell by nearly two thirds. The effect is particularly dramatic inthe consumption of fat, with the combination of fenfluramine and DHEAresulting in approximately 9 Kcal consumption of fat, as compared toapproximately 34 Kcal consumption of fat in the control group. Theanimals were neither sick nor hyperactive. There was no obviousbehavioral change that could account for this change.

EXAMPLE 2

This experiment is similar to example 1, except that obese, rather thanlean, Zucker rats were used as the animal model.

The protocol was the same as in example 1. The results show an effect onintake with individual use of fenfluramine and DHEA. Fenfluramine causesa decrease in carbohydrate and protein intake, and DHEA reduces theintake of protein and fat for the obese animal. Most significantly, thecombination of fenfluramine and DHEA is dramatically effective incurbing all food intake.

The obese rat is a model of youth-onset obesity, while the lean rat is amodel of normal food-intake control mechanism. The results are mostunexpected in the obese animal, as the obese animal's life is centeredon eating; it usually spends its day sitting in its cage nibbling.Results showing a complete inhibition of food consumption for thisanimal are striking. Because this effect is also demonstrated in thelean animal, the results suggest the treatment has universalapplicability for lean and obese subjects.

EXAMPLE 3

The effect on body weight of lean and obese Zucker rats withadministration of fenfluramine and DHEA, given individually and incombination, is determined. The change in body weight of the lean ratsdescribed in FIG. 1 is given in FIG. 3A and the change in body weight ofthe obese rats described in FIG. 2 is given in FIG. 3B. For each groupthe increment of weight is expressed as a percentage of the initial bodyweight.

The control lean animals gained an additional 4% during the time of theexperiment. Animals treated with fenfluramine or DHEA individually alsogained weight, but at a slower rate. Surprisingly, the lean animalsreceiving fenfluramine and DHEA in combination actually lost weight.

Qualitatively, the results are the same with obese animals. The controlanimals gained weight and animals receiving DHEA or fenfluramineindividually maintained their initial weight. Again, with administrationof a combination of fenfluramine and DHEA, the animals showed asignificant weight loss.

EXAMPLE 4

The problem with all currently available anorectic agents is thedevelopment of tolerance to the anorectic action within a short periodof time. This experiment evaluates the long-term effects (28 days) ofadministration of fenfluramine and DHEA on lean Zucker rats, and whethertolerance develops to these drugs.

Four groups of four lean Zucker rats were established. One groupreceived 5 mg/kg/day fenfluramine; a second group received rat chowsupplemented with 0.6% DHEA; a third group received 5 mg/kg/dayfenfluramine and rat chow supplemented with 0.6% DHEA; and a fourthgroup (control) received no medication. The weight of the food consumedon the indicated days is reported as calories in FIG. 4A and the weightof the animals on the corresponding days is recorded in FIG. 4B.

In this experiment rat chow was used as food. DHEA was administered as adietary supplement rather than as a daily injection.

DHEA administered individually had no significant effect on the foodintake of lean animals as the DHEA-treated animals consumed as much chowas the control animals. Fenfluramine administered individually caused aninitial decrease in the consumption of the rat chow, but the effectwaned by three weeks. The combined therapy of fenfluramine and DHEAagain showed effectiveness in reducing food intake, even after 28 days.

Changes in body weight of the treated animals corresponded to changes incaloric intake. FIG. 4B shows that animals treated with eitherfenfluramine or DHEA alone continued to gain weight. In contrast,animals receiving fenfluramine and DHEA in combination lost weight andstayed at this reduced weight.

EXAMPLE 5

This experiment is similar to example 4, except that obese, rather thanlean, Zucker rats were used as the animal model. The protocol was thesame as in example 4.

Fenfluramine administered individually produced a slightly significantdepression in caloric intake on day 15. However, tolerance to the drugwas evident by day 20 and 25. Administration of fenfluramine resulted ina small decrease in body weight in the obese animal. DHEA administeredindividually decreased food intake and stabilized the animals' weightgain.

In contrast to the poor results obtained with individual administrationof the two drugs, favorable results showing a continued suppression offood intake and a weight loss were again obtained with the combined useof DHEA and fenfluramine.

EXAMPLE 6

The effect of mazindol and DHEA individually and in combination on thecarbohydrate intake and body weight of lean Zucker rats was determined.

A first group of five animals was treated with 5 mg/kg/day mazindol, anda second group of five animals was treated with 5 mg/kg/day mazindol and100 mg/kg/day DHEA for three days. A third group received 100 mg/kg/dayDHEA for three days, and a fourth control group of five animals receivedonly vehicle. FIG. 6A shows the carbohydrate intake on day 3, FIG. 6Bshows the change in body weight on day 4, and FIG. 6C shows the totalcaloric intake on day 3 of the test.

The control group showed the largest carbohydrate intake, increase inbody weight, and total caloric intake, followed by the groupadministered mazindol alone, and the group administered DHEA alone. Thegroup receiving the combination of mazindol and DHEA evidenced the mostsignificant decrease in carbohydrate intake, body weight, and totalcaloric intake.

EXAMPLE 7

The effect of phentermine HCl and DHEA individually and in combinationon fat intake and body weight of lean Zucker rats was determined.

A first group of five animals was treated with 7.5 mg/kg/day phentermineHCl, and a second group of five animals was treated with 7.5 mg/kg/dayphentermine HCl and 100 mg/kg/day DHEA for three days. A third groupreceived 100 mg/kg/day DHEA, and a fourth control group of five animalsreceived only vehicle. FIG. 7A shows the daily fat intake, and FIG. 7Bshows body weight gain over the trial.

The control group showed the greatest fat intake and increase in bodyweight, followed by the group administered DHEA alone, and the groupadministered phentermine HCl alone. The group receiving the combinationof phentermine HCl and DHEA evidenced the most significant decrease infat intake and body weight.

EXAMPLE 8

The effect of diethylpropion HCl and DHEA individually and incombination on fat intake, carbohydrate intake, and body weight of leanZucker rats was determined.

A first group of five animals was treated with 10 mg/kg/daydiethylpropion HCl, and a second group of five animals was treated with10 mg/kg/day diethylpropion HCl and 75 mg/kg/day DHEA for three days. Athird group received 75 mg/kg/day DHEA, and a fourth control group offive animals received only vehicle. FIG. 9A shows the fat intake, FIG.9B shows the carbohydrate intake, and FIG. 9C shows body weight gainover the trial.

The group administered the combination of drugs showed the greatestdecrease in fat intake. The carbohydrate intake and body weight resultsfor the various combinations were inconclusive.

EXAMPLE 9

The effect of corticosterone (Compound B) and DHEA individually and incombination on body weight and tissue weight of lean Zucker rats wasdetermined.

Six groups of animals were established: the first (control) group; asecond group receiving an injection of 1 mg/kg/day corticosterone insesame oil ("Cpd B 1"); a third group receiving an injection of 5mg/kg/day corticosterone in sesame oil ("Cpd B 5"); a fourth groupreceiving a diet supplemented with 0.3% DHEA ("DHEA"); a fifth groupreceiving 1 mg/kg/day corticosterone in sesame oil and a dietsupplemented with 0.3% DHEA ("Cpd B 1+DHEA"); and a sixth groupreceiving an injection of 5 mg/kg/day corticosterone in sesame oil and adiet supplemented with 0.3% DHEA ("Cpd B 5+DHEA").

The animals were fed a "macronutrient selection" diet. The controlanimals gained the most weight. Animals receiving the lower dose ofcorticosterone gained almost the same amount as the control animals.Animals receiving the larger dose of corticosterone and animalsreceiving the DHEA-supplemented diet gained weight, although not asrapidly as the control group and the group receiving the lower dose ofcorticosterone.

Surprisingly, neither of the groups receiving the combination of DHEAand corticosterone gained weight. In fact, the group receiving thelarger dose of corticosterone along with DHEA showed a profound weightloss: the weight of the animals fell to 94% of the original weight.

On the last day of the experiment, all animals were sacrificed andtissues were removed. The effect of the therapies on epididymal,perirenal, and retroperitoneal fat pads was measured. FIG. 10. Theweights of the tissues were expressed as percentages of the weights ofthe control tissues. In each case, treatment with the higher dose ofcorticosterone caused the greatest weight gain.

In contrast to these results, treatment with corticosterone and DHEAproduced a decrease in tissue weight, and at the highest dose ofcorticosterone, the values obtained are statistically different fromboth of the corticosterone-alone treated animals.

The effect of these therapies on the soleus muscle is shown in FIG. 10.The weights of the muscle were not affected by DHEA. This indicates thatat least some of the weight loss caused by the combined treatment wascaused by a preferential loss of fat.

EXAMPLE 10

Metabolites of DHEA, such as Δ4-androstenedione, may substitute for DHEAin the process of the invention. In the present example, the effect ofΔ4-androstenedione, on feeding inhibition in lean and obese Zucker ratswas determined.

Two groups of five lean animals and two groups of five obese animalswere fed control chow for seven days, during which basal caloric intakewas measured. A seven day feeding of various concentrations ofΔ4-androstenedione determined that concentrations of 0.6 and 0.3%Δ4-androstenedione significantly reduced intake. A final seven dayfeeding of control chow resulted in an "overshoot" of intake abovepre-treatment levels.

After Δ4-androstenedione administration, neurotransmitter content of keyhypothalamic feeding centers was measured, including lateral (LH),ventromedial (VMH), and paraventricular (PVN) hypothalamus. After 1 dayand seven days of Δ4-androstenedione, the obese Zucker rats exhibited anincreased metabolism of 5-HT in LH and PVN, respectively. In addition,dopamine conversion to norepinephrine was increased in VMH.

Serum insulin and Δ4-androstenedione were measured in control andexperimental lean and obese Zucker rats. Oral Δ4-androstenedione yieldedincreased serum Δ4-androstenedione levels compared to their respectivecontrols, indicating that the steroid was in the circulation of theanimal. After 1 day of Δ4-androstenedione, insulin levels dropped in theobese Zucker rat, but not in the lean Zucker rat, even thoughconsumption of chow decreased markedly in both phenotypes 24 hoursbefore the animals were sacrificed.

The obese Zucker rat showed a trend toward decreased basalΔ4-androstenedione serum levels compared to the lean Zucker rat. Thesedata suggest that DHEA conversion to Δ4-androstenedione is different inlean and obese rats.

The experimental results show a consistent decrease in the amount offood an obese or lean animal consumes having a particularly strikingeffect on dietary fat consumption with administration of DHEA and atleast one anorectic agent. Most in contrast to treatments currently usedto treat obesity and related disorders, the results demonstrate thattolerance to the composition of the invention does not develope over a28 day period. Given the known activities of DHEA, and the anorecticagents fenfluramine HCl, phentermine HCl, phendimetrazine tartrate,mazindol, diethylpropion HCl, and fluoxetine HCl administeredindividually, the effect of the combination of the drugs is striking. Itis significant that the experimental results were generated not only inthe obese animal, which may be a model for some pathologic states ofhuman obesity, but also in the lean animal, the food intake of which isprobably a better reflection of normal physiology.

In summary, the combined use of DHEA and an anorectic agent can be aclinically effective treatment for human or animal obesity and relateddisorders. Currently, there is no other combination that promises to beas effective as the newly discovered combination.

Having now fully described the invention, it will be apparent to one ofordinary skill in the art that many changes and modifications can bemade thereto without departing from the spirit or scope of the inventionas set forth herein. The appended claims are not intended to belimiting.

We claim:
 1. A method for treating obesity in an animal comprisingadministering a therapeutically effective amount of a compositioncomprising dehydroepiandrosterone (DHEA) or a derivative thereof and atleast one anorectic agent selected from the group consisting offenfluramine hydrochloride (HCl), phentermine HCl, phendimetrazinetartrate, mazindol, diethylpropion HCl, and fluoxetine HCl, and furthercomprising the administration of a glucocorticoid.
 2. A method fortreating obesity in an animal as claimed in claim 1 wherein thederivative of dehydroepiandrosterone (DHEA) is selected from the groupconsisting of 16-substituted androstanes, 16-substituted androstenes,17-hydroxy-steriods, α-HET, β-HET, and Δ4-androstenedione.
 3. A methodfor treating obesity in an animal as claimed in claim 1 wherein thederivative of dehydroepiandrosterone (DHEA) is Δ4-androstenedione. 4.The method according to claim 1, wherein the glucocorticoid iscorticosterone.
 5. The method according to claim 4, wherein thecorticosterone is administered from about 1 mg/kg/day up to about 50mg/kg/day.
 6. The method according to claim 5, wherein thecorticosterone is administered from about 5 mg/kg/day up to about 25mg/kg/day.
 7. A method for treating hyperphagia in an animal comprisingadministering a therapeutically effective amount of a compositioncomprising dehydroepiandrosterone (DHEA) or a derivative thereof and atleast one anorectic agent selected from the group consisting offenfluramine hydrochloride (HCl), phentermine HCl, phendimetrazinetartrate, mazindol, diethylpropion HCl, and fluoxetine HCl.
 8. A methodfor treating hyperphagia in an animal as claimed in claim 7 wherein thederivative of dehydroepiandrosterone (DHEA) is selected from the groupconsisting of 16-substituted androstanes, 16-substituted androstenes,17-hydroxy-steriods, α-HET, β-HET, and Δ4-androstenedione.
 9. A methodfor treating hyperphagia in an animal as claimed in claim 7 wherein thederivative of dehydroepiandrosterone (DHEA) is Δ4-androstenedione. 10.The method according to claim 7, wherein the composition is administeredeither orally or parenterally.
 11. The method according to claim 10,wherein DHEA or a derivative thereof, the anorectic agent, or both areadministered by a method selected from the group consisting of a foodsupplement, a transdermal patch, a rectal suppository, and by injection.12. The method according to claim 7, wherein the animal is a human. 13.The method according to claim 7, further comprising the administrationof a glucocorticoid.
 14. The method according to claim 13, wherein theglucocorticoid is corticosterone.
 15. The method according to claim 14,wherein the corticosterone is administered from about 1 mg/kg/day up toabout 50 mg/kg/day.
 16. The method according to claim 15, wherein thecorticosterone is administered from about 5 mg/kg/day up to about 25mg/kg/day.
 17. The method according to claim 7, wherein the compositionfurther comprises a pharmaceutically acceptable carrier.
 18. Apharmaceutical composition for treating obesity or a related disorder inan animal comprising dehydroepiandrosterone (DHEA) or a derivativethereof and at least one anorectic agent selected from the groupconsisting of fenfluramine hydrochloride (HCl), phentermine HCl,phendimerazine tartrate, mazindol, diethylpropion HCl, and fluoxetineHCl, and further comprising the presence of a glucocorticoid.
 19. Thepharmaceutical composition according to claim 18, wherein theglucocorticoid is corticosterone.
 20. The pharmaceutical compositionaccording to claim 19, wherein the corticosterone is present in anamount from about 1 mg/kg/day up to about 50 mg/kg/day.
 21. Thepharmaceutical composition according to claim 20, wherein thecorticosterone is present in an amount from about 5 mg/kg/day up toabout 25 mg/kg/day.
 22. A pharmaceutical composition for treatingobesity as claimed in claim 18 wherein the derivative ofdehydroepiandrosterone (DHEA) is selected from the group consisting of16-substituted androstanes, 16-substituted androstenes,17-hydroxy-steriods, α-HET, β-HET, and Δ4-androstenedione.
 23. Apharmaceutical composition for treating obesity as claimed in claim 18wherein the derivative of dehydroepiandrosterone (DHEA) isΔ4-androstenedione.